NMRNMR SpectroscopySpectroscopy forfor StudyingStudying ChiralityChirality
ThomasThomas J.J. WenzelWenzel DepartmentDepartment ofof ChemistryChemistry BatesBates CollegeCollege Lewiston,Lewiston, MaineMaine 0424004240 [email protected]@bates.edu
ChiralChiral DiscriminationDiscrimination NMRNMR SpectroscopySpectroscopy
•• ChiralChiral derivatizingderivatizing agentsagents
•• ChiralChiral solvatingsolvating agentsagents
•• MetalMetal complexescomplexes
•• LiquidLiquid crystalscrystals ChiralChiral DerivatizingDerivatizing AgentsAgents
•• FormForm aa covalentcovalent bondbond betweenbetween anan opticallyoptically purepure reagentreagent andand thethe compoundcompound ofof interestinterest
CDACDA ++ (( RR))--SubSub == CDACDA --((RR))--SubSub CDACDA ++ (( SS))--SubSub == CDACDA --((SS))--SubSub
•• ResultingResulting compoundscompounds areare diastereomersdiastereomers ChiralChiral DiscriminatingDiscriminating AgentsAgents
•• NoNo racemizationracemization
•• NoNo kinetickinetic resolutionresolution
•• NeedNeed 100%100% opticaloptical puritypurity ofof thethe reagentreagent ifif usingusing forfor thethe determinationdetermination ofof enantiomericenantiomeric excessexcess ChiralChiral SolvatingSolvating AgentsAgents
•• FormForm nonnon --covalentcovalent interactionsinteractions betweenbetween anan opticallyoptically purepure reagentreagent andand thethe compoundcompound ofof interestinterest
CSACSA ++ (( RR))--SubSub == CSACSA --((RR))--SubSub CSACSA ++ (( SS))--SubSub == CSACSA --((SS))--SubSub
•• ResultingResulting compoundscompounds areare diastereomersdiastereomers
•• KKR andand KK S areare likelylikely differentdifferent –– causescauses differentdifferent timetime --averagedaveraged solvationsolvation environmentsenvironments ChiralChiral SolvatingSolvating AgentsAgents
•• PreferablePreferable toto havehave fastfast exchangeexchange
•• HighHigh concentrationconcentration ofof CSACSA usuallyusually leadsleads toto largerlarger discriminationdiscrimination
•• OftenOften seesee enhancedenhanced enantiomericenantiomeric discriminationdiscrimination atat lowerlower temperaturestemperatures AssigningAssigning AbsoluteAbsolute StereochemistryStereochemistry
•• MechanismMechanism ofof discriminationdiscrimination isis understoodunderstood andand characteristiccharacteristic shiftsshifts occuroccur inin thethe spectrumspectrum – More common with certain families of chiral derivatizing agents – Possible with some chiral solvating agents
•• EmpiricalEmpirical trendtrend – Best if use known model compounds as close as possible in structural features to the unknown ArylAryl --containingcontaining CarboxylicCarboxylic AcidsAcids --AlcoholsAlcohols andand AminesAmines
CH3O O O O F H3CO HC3CO OH F3C C COH OH H3C C COOH O
CN
CFTA MTPA MPA (O-MMA) O-AMA
OCH3
OH
O OCH3 O H N H3C C COOH OH O
H3CO OH
N-Boc PG MαNP 2-AMA/9-AMA ArylAryl --containingcontaining CarboxylicCarboxylic AcidsAcids
•• MTPAMTPA == αα--methoxymethoxy --αα-- trifluoromethylphenylacetictrifluoromethylphenylacetic acidacid •• MPAMPA == αα--methoxyphenylaceticmethoxyphenylacetic acidacid •• OO--AMAAMA == OO--acetylacetyl mandelicmandelic aciedacied •• CFTACFTA == αα--cyanocyano --αα--fluorofluoro --pp--tolylacetictolylacetic acidacid •• NN--BocBoc PGPG == NN--bocboc phenylglycinephenylglycine •• MMααNPNP == 22 --methoxymethoxy --22--(1(1 --naphthyl)propionicnaphthyl)propionic acidacid •• 22--/9/9 --AMAAMA == αα--(2(2 --anthryl)anthryl) --αα--methoxyaceticmethoxyacetic acidacid Mosher Method/Modified Mosher Method
-Prepare derivatives with (R)- and (S)-forms of the reagent -Syn-periplanar arrangement of HC-O-C(O)-C atoms (secondary alcohols) ∆δ RS -Calculate values – negative for L 1, positive for L 2
(OMe) (Ph) (R)-MTPA
L1 Ph OMe (S)-MTPA O L2 CF3
H O OH H1 8 9
∆δRS 7 5 3 H1' 8 6 4 RO Me(10) Me(8) Me(9) H2
MTPA 0.07 -0.017 -0.04 Position MTPA MPA PPA 1 0.07 0.19 0.43 MPA 0.05 -0.021 -0.26 1' 0.03 0.12 0.20 2 0.09 0.14 0.18 3 0.04 0.02 0.03 10 4 0.03 0.07 0.14 4' 0.03 0.06 0.13 8 0.03 0.04 0.10 PPA = α-phenyl- propionic acid
∆δ RS depends on:
-Degree of conformational preference/how it influences the shielding -Size of the shielding (anthryl > naphthyl > phenyl) SecondarySecondary AlcoholsAlcohols
•• MPAMPA >> MTPAMTPA (conformational(conformational preferencepreference thatthat producesproduces greatergreater differencedifference inin shielding)shielding) •• MPAMPA –– earlyearly syntheticsynthetic proceduresprocedures –– highhigh degreedegree ofof racemizationracemization •• BetterBetter proceduresprocedures forfor MPAMPA derivatizationderivatization nownow existexist •• MixMix andand shakeshake methodmethod MPA derivative
I
OH
2.7 Hz differential shielding for the methyl group 9-bonds removed From the chiral center EffectEffect ofof temperaturetemperature
•• ForFor MPAMPA derivativesderivatives ofof secondarysecondary alcohols,alcohols, loweringlowering thethe probeprobe temperaturetemperature byby aboutabout 100100 KK (to(to 175175 --200K)200K) approximatelyapproximately doublesdoubles thethe ∆δ∆δ RS valuesvalues •• AltersAlters conformationalconformational preferencepreference furtherfurther towardtoward thethe spspformform ∆δ∆δ •• CanCan measuremeasure T1T2 valuesvalues asas aa confirmationconfirmation ofof stereochemicalstereochemical assignmentassignment •• EffectEffect notnot asas pronouncedpronounced withwith MTPAMTPA oror AMAAMA BariumBarium MethodMethod MPA/secondaryMPA/secondary alcoholsalcohols
sp ap
MeO O Ph O
H H α α' O Ph O MeO L2 L2
L1 L1 Ba+2 Ba+2 Barium binds in a chelate manner with the ester and
Ba+2 alters the conformation MeO O Ph O preference toward the sp H H α α' O conformer. Ph O O L2 Me L2 Ba+2 L L 1 1 Leads to enhancement in +2 +2 sp-Ba complex ap-Ba complex the shielding and get larger ∆δ RS values. La(hfa)La(hfa) 3 methodmethod withwith MTPAMTPA SecondarySecondary alcoholsalcohols
R2 MeO R2 OMe R R1 1 X X CF CF3 3 Chelate bonding of the H O H O sp sp La reverses the orientation of the phenyl ring and the
R2 R2 F3C CF3 R1 R1 shifts of the hydrogen X X OMe OMe resonances H O M H O M sp' sp'
(S)-MPTA derivative (R)-MPTA derivative
X = O or NH This reversal in shifts
(b) can be used to confirm ∆δ S,R ∆δ S,R 0 < 0 OMTPA 0 > 0
M R1 R2 M the stereochemical H assignment ∆δ S,R > 0 ∆δ S,R < 0 M MTPA plane M 22--AMA/9AMA/9 --AMAAMA –– LinearLinear vsvs cycliccyclic secondarysecondary carbinolscarbinols
Me
Me O MeO H
H R1 R2 H
O O
H
MeO H MeO
R1 R2 H MMααNPNP (secondary(secondary alcohols)alcohols)
OCH3
H3C C COOH
-∆δ RS about 4-times greater than with MTPA
-Less prone to racemization with methyl group on chiral carbon CFTACFTA (secondary(secondary alcohols)alcohols)
F
H3C C COOH
CN
•• TheThe ∆δ∆δ RS valuesvalues areare typicallytypically 22 --timestimes greatergreater thanthan MTPAMTPA •• MuchMuch fasterfaster reactionreaction thanthan MTPAMTPA withwith hinderedhindered compoundscompounds •• 1HH andand 19 FF NMRNMR cancan bebe usedused CFTA - Conformational Preference syn-periplanar arrangement
N Me C
O
RR RS F
O H
CFTA ester plane SecondarySecondary DiolsDiols andand PolyolsPolyols
•• IfIf groupsgroups areare farfar enoughenough apart,apart, cancan determinedetermine thethe configurationconfiguration ofof eacheach groupgroup independentlyindependently
•• IfIf groupsgroups areare closeclose together,together, boundbound reagentreagent maymay influenceinfluence thethe shieldingshielding oror deshieldingdeshielding atat moremore thanthan oneone sitesite MPAMPA forfor DiolsDiols
•• AnalysisAnalysis ofof (( synsyn andand antianti):): –– 1,21,2 -- –– 1,31,3 -- –– 1,41,4 -- –– 1,51,5 --diolsdiols withwith knownknown configurationsconfigurations
•• ObserveObserve reproduciblereproducible trendstrends thatthat cancan bebe appliedapplied toto compoundscompounds withwith unknownunknown configurationsconfigurations PrimaryPrimary AlcoholsAlcohols
•• MTPAMTPA –– CC2 chiralchiral
•• CFTACFTA O OMOM
OMe O EtOOC ∗ OH ∗ OH 2.116
•• 99--AMAAMA O
HO N Cl 1' MeO H N α 2' O N N H L2 MPA - Unreliable Ar L1 TertiaryTertiary AlcoholsAlcohols
2-NMA
MTPA (a)
(H) (Nap) (S)-2NMA HC HB HA Nap (R)-2NMA OH H CH2 O HX HY HZ OMe
CH2 2NMA plane Me O
HX O-2NMA (b) HC
H2 H2 ∆δ ∆δ HY < 0 C C C > 0 HB
HZ Me HA SecondarySecondary AminesAmines
•• MTPAMTPA
O
N N CF3 N
MTPA OMe MTPA Ph 2
∆δ∆δ RS •• HH2 hadhad aa ofof 2.442.44 ppmppm !! •• ValuesValues soso largelarge onlyonly needneed oneone MTPAMTPA derivativederivative (use(use (( RR))--acidacid chloridechloride sincesince moremore reactivereactive thanthan (( SS))--acidacid chloride)chloride) PrimaryPrimary AminesAmines –– αα--substitutedsubstituted
•• MTPAMTPA givesgives largerlarger ∆δ∆δ RS valuesvalues thanthan MPAMPA oror 99--AMAAMA -- MTPAMTPA amidesamides havehave greatergreater preferencepreference forfor thethe spsp conformerconformer thanthan observedobserved withwith esters.esters.
•• BPGBPG –– preferencepreference forfor apap conformerconformer –– typicaltypical ∆δ∆δ RS valuesvalues areare 22 -- toto 33 --timestimes largerlarger thanthan withwith
MTPAMTPA O
H N OH ArylAryl MethoxyMethoxy ReagentsReagents -- SummarySummary
•• WantWant largerlarger ∆δ∆δ RS valuesvalues –– eithereither throughthrough highhigh conformationalconformational preferencepreference oror largerlarger aromaticaromatic ringring (shielding)(shielding) •• ValuesValues shouldshould allall bebe positivepositive forfor oneone
substituentsubstituent (L(L 1)) andand negativenegative forfor thethe otherother (L(L 2)) •• NeedNeed resonancesresonances inin bothboth substituentssubstituents O
O CamphanicCamphanic AcidAcid
O HO
•• propro-- ((RR)) andand propro-- ((SS)) positionspositions ofof αα--deuterateddeuterated primaryprimary andand secondarysecondary alcoholsalcohols
D O D H H D H
R OH HO Ph N OH
H D O D H Ph H
•• PrimaryPrimary aminesamines asas wellwell 22--(2,3(2,3 --Anthracenedicarboximido)Anthracenedicarboximido) -- cyclohexanecyclohexane carboxyliccarboxylic acidacid O
N
HOOC
O Analysis of primary and secondary alcohols – especially effective for compounds with remotely disposed chiral centers
O O (Me) (Me)
N O ∗ Me O Me
O
O O
N
O 2,2,22,2,2 --TrifluoroTrifluoro --11--(9(9 --anthryl)ethanolanthryl)ethanol (TFAE)(TFAE) (( PirklePirkle ’’ss Alcohol)Alcohol)
H F3C C OH
Versatile chiral solvating agent -Can determine optical purity -Can assign absolute configurations for certain classes of compounds AbsoluteAbsolute ConfigurationsConfigurations -- TFAETFAE Sulfoxides
H H O O O O
C6H5 i-propyl C6H5 CH3 C S C S N-oxides
CF3 H CH3 CF3 H i-propyl (R,R) (R,S) H O O Amino Acids CH3
CH2 C O O N H H H H H H3C CH3 CF3 N C N C H C C OCH3 OCH3 H CH3 H H
O O C C
H H CF3 CF3 AbsoluteAbsolute ConfigurationsConfigurations -- TFAETFAE
Oxaziridines Imines
H CF3 H CF3
C C H R H R R1 O R1 O O N O N H CA,B CA,B H CF CF3 2 2 3 C O C O Me Me
Ph H Ph H CN CN Ph CH3 Me1 C Me1 C CH Ph H 3 H
(R,R)(R,S)
Lactones Lactams
HO HO
O C R1 O C R2
Ar Ar C O R2 C O R1 N O H F3C H F3C TFAETFAE –– EnantiomericEnantiomeric PurityPurity
2,3-diamino succinate – methine Epoxides signals for mesoversus dl-isomers
R1 R2 NH2 O
-O CC O- 3 H O R O NH2 Axial Chiral Compounds Slow Rotation
O R R R R N N X OCH3 O O
H N CH O 3 N
R1 R2 N
X = Cl X = NO2 1 2 3 1 a (R = i-Pr) X = CH3 R = Cl CH3 CH3 2 R = HHCH3 b (R = Et) TFAETFAE –– EnantiomericEnantiomeric PurityPurity
Metal Complexes 1
Cl Cl O Nb S Nb S S S O Pd
N N Cl
Ar Ar
Phosphine Oxides Calixarenes
O O Pr Pr O PrO O PrO Ph P(OCH CH ) Ph P(OCH2CH3)2 2 3 2
Cr(CO)3 ON ON AlcoholsAlcohols asas CDAsCDAs forfor CarboxylicCarboxylic AcidsAcids
O •• MethylMethyl mandelatemandelate H C COCH3
OH
O •• MentholMenthol HO N HO
O •• 22--(2,3(2,3 --anthracenedicarboximido)anthracenedicarboximido) --11--cyclohexanolcyclohexanol GlycosidationGlycosidation ShiftsShifts
•• ReactReact secondarysecondary alcoholalcohol withwith DD --glucoseglucose oror DD--mannosemannose •• PronouncedPronounced differencesdifferences inin thethe 13 CC NMRNMR spectrumspectrum thatthat correlatecorrelate withwith absoluteabsolute configurationconfiguration –– seesee trendstrends inin bothboth sugarsugar andand alcoholalcohol resonancesresonances •• AlsoAlso seesee differencesdifferences inin thethe 1HH NMRNMR spectrumspectrum ofof secondarysecondary alcoholsalcohols withwith tetratetra -- OO--acetylglucoseacetylglucose ββ--DD-- andand ββ--LL--FucofuranosideFucofuranoside andand
ArabinofuranosideArabinofuranoside OH HO •• UseUse tetraacetatetetraacetate derivativederivative ofof sugarsugar O HO ((arabinoarabino easiereasier toto prepare)prepare) CHOH
•• ReactReact withwith secondarysecondary oror tertiarytertiary CH3 alcoholalcohol •• AlsoAlso worksworks withwith 1,21,2 --glycolsglycols •• AlkalineAlkaline hydrolysishydrolysis ofof acetateacetate groupsgroups •• SeeSee differencesdifferences inin thethe 1HH andand 13 CC spectraspectra ofof productproduct thatthat correlatecorrelate withwith absoluteabsolute configurationconfiguration 2,22,2 ’’--DihydroxyDihydroxy --1,11,1 ’’binaphthalenebinaphthalene (BINOL)(BINOL)
•• PotentialPotential chiralchiral solvatingsolvating
agentagent forfor severalseveral classesclasses ofof OH
substratessubstrates includingincluding alcohols,alcohols, OH sulfoxidessulfoxides ,, selenoxidesselenoxides ,, amines,amines, ketonesketones ,, amides,amides, andand aminoamino alcoholsalcohols
OH OH
O O
OH S OH S CH CH3 Ph 3 Ph
(S) (R) ButaneButane --2,32,3 --diol/Butanediol/Butane --2,32,3 --thiolthiol
•• ChiralChiral derivatizingderivatizing agentagent forfor thethe analysisanalysis ofof chiralchiral ketonesketones –– produceproduce diastereomericdiastereomeric ketalsketals
Me O Me O
O RS RS
•• ForFor cyclohexanonescyclohexanones inin thethe chairchair conformation,conformation, thethe 13 CC shiftsshifts correlatecorrelate withwith absoluteabsolute stereochemistrystereochemistry
X = CH2 O O S O
X PEA,PEA, NEANEA andand AEAAEA
CH3CH NH2 CH3CH NH2 CH3CH NH2
Useful with carboxylic acids -chiral solvating agent – formation of diastereomeric salts -chiral derivatizing agent – formation of amides – can assign absolute stereochemistry with certain compounds
O H O H O H Me H H Et Et Me
Me Me Me Et N Me N H N Ph Ph Ph H H H H H H H H H
i (major) ii (major') iii (minor)
O H O H O H H Me Et H Me Et
Me Me Me Et N Me N H N Ph Ph Ph H H H H H H H H H PEA,PEA, NEANEA andand AEAAEA
R
Me P S • PhosphorusPhosphorus thioacidsthioacids • OH
O H •• PhosphonicPhosphonic acidsacids R C POH OH OH
•• SulfonylSulfonyl chlorideschlorides
O CH2SO2Cl
•• IsocyanatesIsocyanates O
OCN OR'
R PEA,PEA, NEANEA andand AEAAEA -- KetonesKetones
•• MethodMethod 11
–– ConvertConvert toto acidacid oximeoxime usingusing NHNH 2OCHOCH 2COOHCOOH –– AddAdd NEANEA toto formform saltsalt –– seesee discriminationdiscrimination
•• MethodMethod 22 –– ReductivelyReductively aminateaminate thethe enoneenone withwith PEAPEA perchlorateperchlorate –– seesee discriminationdiscrimination inin productsproducts PhenylglycinePhenylglycine methylmethyl esterester andand dimethyldimethyl
O amideamide (PGME)(PGME) H H3CO C C NH2 AbsoluteAbsolute configurationconfiguration ofof carboxyliccarboxylic acidsacids –– ∆δ∆δ RS valuesvalues α-Substituted
HA HB HC (H) (Ph) (R) O Ph H (S)
HZ HY HX Z
PGME (PGDA) plane H H O β β H O , -substituted acids R1 N R 2 OMe
H H O
PGME plane PGMEPGME -- examplesexamples
HOOC
O Me H OH COOMe O O
H O
Me
OH H Me O H H H O OH Me O O Me Me H O Me COOH H H H O H O Me H OH
O H H HO H HO O H
HO H
Me
HO O H H H O Me O O COOH 1,21,2 --DiphenylDiphenyl --1,21,2 --diaminoethanediaminoethane
H2N NH2
CH HC
3-substituted cyclohexanones and cyclopentanones -forms the corresponding aminal -can determine enantiomeric purity
Ph Ph Ph Ph O
Ph Ph HN NH HN NH
H N NH * 2 2 n R * * n R n R - - Ph Ph 1,2 1,2 * * - - N N R * diphenyl diphenyl - - Ph HN diaminoethane diaminoethane NH Ph Substituted 1,2 Substituted Substituted 1,2 Substituted - - ’ ’
N N imidazolidine corresponding the -forms enantiomeric determine to used be -can purity * , , RCHO Reacts with Aldehydes with Reacts N N 3 2 CH COH O 2 NO 3 H C CH CH CH 3 O CH C H C 3 NH H N NH H C O N 2 O C O N N 2 2 O N N O 2 2 O O Soluble Pirkle Soluble Phases LC Amides as Chiralas Amides Agents Solvating -(3,5-Dinitrobenzoyl)- -(3,5-Dinitrobenzoyl)-L-leucine -(3,5-Dinitrobenzoyl)-4-amino- Anthrene (Whelk-O-1) N (DNB-PEA) 1-phenylethylamine N (DNB-Leu) N 3-methyl-1,2,3,4-tetrahydrophen- PhosphorusPhosphorus --basedbased ReagentsReagents
•• P(V)P(V) reagentsreagents (P=O(P=O oror P=S)P=S) groupgroup •• P(III)P(III) reagentsreagents
•• P(V)P(V) reagentsreagents areare moremore stablestable thanthan P(III)P(III) reagentsreagents butbut usuallyusually havehave smallersmaller enantiomericenantiomeric discriminationdiscrimination
•• 31 PP signalsignal usuallyusually monitoredmonitored –– splitssplits intointo twotwo singletssinglets forfor thethe twotwo diastereomersdiastereomers forfor derivatizingderivatizing agentsagents P(V)P(V) ReagentsReagents -- ExamplesExamples
CH3
CH3 N S H P O Ph Cl O O Ph P Ph O O N CH Cl 3 P O P CH3 Cl O PN Ph N O O Cl P O Cl Cl O Ph
-Alcohols and amines react at the chlorine atom
-Primarily used for determining enantiomeric purity Configurational analysis of thiophosphate S monoester that is chiral by virtue of =18O 16 different oxygen isotopes P O = O OEt O
S Ph O Cl Me + P H P O OEt H N O Me 18 O and 16 O in the S O Ph Ph OEt O P S O bridging position have Me Me O P H P + H P OEt O O different effects on the H N H N Me Me shift of the phosphorus
Ph Ph resonance O O S Me O O O Me H P + H P OEt O P H N P H N Me S Me OEt
=18O O =16O PhosphinothioicPhosphinothioic AcidsAcids Ph S Ph S
P P
t Me OH Bu OH
Ph S H O R Ph S H O Ph P P P P
R Ph R O H S O H S R
Effective chiral solvating agents for:
-Phosphine oxides -Alcohols/Diols -Phosphonates -Amines -Sulfoxides -Thiols -Amine oxides -Amino alcohols CF3
P(III)P(III) ReagentsReagents Me Me Me NH NH NH
NH NH R1 R1 NH Me Me Me R2 N R2 N CF3 CH3 Phos13 Phos14 P Cl P N Phos15
CH3 R2 N R2 N
R1 R1 CH3 CH3 CH3
N N N
N N N
CH CH -Primary, secondary and 3 CH3 3 tertiary alcohols Phos16 Phos18 -Thiols Phos17
CH -Carboxylic acids 3 N α NH - -hydroxyphosphonates NH NH
CH3
Phos19 Phos20 CO R HO 2 OH O P(III)P(III) ReagentsReagents OH HO CO2R OH O HO R = Et or iPr R O Phos21 Phos22 Phos23
P Cl
O R O OH OH H3C OH OH O OH -Primary, secondary and H3C OH tertiary alcohols Phos24 Phos25 Phos26 -Primary amines O
-Carboxylic acids (CH3)2NC OH
(CH3)2NC OH
O
Phos27 [5][5] HELOLHELOL PhosphitePhosphite
MeO OMe -Primary and secondary
OMe alcohols
O -Phenols Cl P OMe -Amines MeO O -Carboxylic acids after coupling to MeO 2-aminophenol
OMe MeO
CH3
OH Ph TRISPHAT,TRISPHAT, BINPHAT,BINPHAT, BINTROPBINTROP
Cl Cl Cl Cl
Cl O O Cl
Cl
O P O Cl Cl Cl Cl
O O
Cl O
O O Cl Cl P
O O
O Cl Cl Cl
Cl Cl
Cl
O
O O P Useful for ionic compounds O O
O TRISPHATTRISPHAT –– MetalMetal ComplexesComplexes
2+
N Cl O
Pd N N (OC)3Cr O O Fe py (R) 7.62 N N
3 R1 O O O 2 R (S)
Ru Mn(CO)3
+ R'' N O (depe)2 Ru S I Ru Me Cp*M Cr(CO)3
R TRISPHAT,TRISPHAT, BINPHATBINPHAT –– OtherOther CationsCations
Me N N O
P CH3 D S4 2 CD3
X X
X = Br, H
NN NN
Pr Pr N N
N
S MeO OMe N Me BF4 BINTROPBINTROP –– LimitedLimited studiesstudies onon anionsanions
R t-Bu
O O
B O O O
R O O t-Bu O O N N
O O N N O O O ConfigurationConfiguration ofof PhosphatesPhosphates ∅ ∅CH O O 3 P P O •• ReactReact (( cyclizecyclize )) withwith O OCH O 3 propanepropane --1,21,2 --dioldiol ∅ ∅CH O 3 O P P O O O OCH3
OCH3 O O O • ReactReact (( cyclizecyclize )) withwith P • P O O ∅ ∅ (S)(S) --22--iodoiodo --11-- CH3
phenylethanolphenylethanol ∅ = 17O = 18O
H H H O O Ph Ph O Ph H O Ø P P P Ph OH Me OMe ØMe S S S O SP H H Ø O H O Ph Ph O Ph Me OMe ØMe P P P O Ø S S S SeleniumSelenium --containingcontaining ReagentReagent 7777 Se SeSe NMRNMR H NO -Carboxylic acids – react at NH group -Alcohols and alkyl halides react at selenium Ph atom -Amines with triphosgene react at the NH group
R O Se Se
S H N O R-OH or R-Br S OH N O H
Ph Ph
Effective for compounds with remotely disposed chiral centers – because of shift range of 77 Se NMR αα--,, ββ-- andand γγ--CyclodextrinsCyclodextrins
HO OH
3 2 1 4 O
5 O
6 OH
Native – underivatized -Water-soluble -Effective for water-soluble substrates -Determination of enantiomeric purity -Substrates usually contain an aromatic ring (phenyl or bicyclic) CyclodextrinsCyclodextrins Permethylated cyclodextrins -β-Derivative is more water-soluble than native β-CD -Organic-soluble as well -Broadly applicable for determining enantiomeric purity -Especially useful for the analysis of allenes
R1 R3 C CC
R2 H - Carboxymethylated (-CH 2CO 2 ) cyclodextrins - Anionic -Especially useful for organic cations -Can add paramagnetic lanthanides – these associate at the carboxy group and cause shifts in the spectra that enhance the enantiomeric discrimination CrownCrown EthersEthers (18-Crown-6)-2,3,11,12-tetracarboxylic acid
O
HOOC O O COOH
HOOC O O COOH
O
Useful for primary amines R -As hydrochloride salts -As neutral amines (neutralization N reaction with crown ether) H O -In methanol, acetonitrile, or water O O H H (usually best in methanol) O O O CrownCrown EthersEthers (18-Crown-6)-2,3,11,12-tetracarboxylic acid
Useful for secondary amines -As neutral amines (neutralization reaction with crown ether) -In methanol -Effective for pyrrolidines, piperidines, piperazines,
alkyl aryl amines R R'
N
O O HOOC O O O H H
O O HOOC COOH O Calix[4]resorcarenesCalix[4]resorcarenes
Sulfonated analog with L-proline OH groups
O -Water-soluble
N -Effective for mono or bicyclic CH2 aromatic compounds – singly or HO OH ortho-substituted
R R R H C
CH2
CH2 (a) (b) SO3 4
R R
(c) (d) LanthanideLanthanide tristris((ββ--diketonatesdiketonates ))
CF3 tfc
O O dcm
O O
CF2CF2CF3 hfc
O Organic-soluble O •• SuitableSuitable forfor aa widewide rangerange ofof hardhard LewisLewis basesbases –– oxygenoxygen -- andand nitrogennitrogen --containingcontaining compoundscompounds –– metalmetal complexescomplexes withwith bindingbinding groupsgroups inin ligandsligands
•• ParamagnetismParamagnetism ofof lanthanidelanthanide ionsions doesdoes causecause broadeningbroadening –– worseworse atat higherhigher fieldfield strengthsstrengths – Use a lower field instrument (300 MHz or lower) – Run 13 C spectra – Use Sm(III ) chelates – Use a polar solvent – Warm the sample (50 -75 oC) ““ChiralizationChiralization ”” ofof XenonXenon
MeO O O O OMe MeO
(CH ) (CH ) (CH2)2 2 2 2 2 OMe MeO O O O OMe
-Racemic cryptophane binds xenon in the cavity
-Addition of Eu(hfc) 3 causes the appearance of two 129 Xe signals LanthanidesLanthanides -- AbsoluteAbsolute ConfigurationConfiguration EmpiricalEmpirical TrendsTrends
•• AlkylAlkyl arylaryl carbinolscarbinols •• BenzhydrolsBenzhydrols •• 22--AryloxypropionylAryloxypropionyl derivativesderivatives •• AminoAmino acidacid methylmethyl estersesters •• MenthylMenthyl butanoatesbutanoates •• NN--phthaloylphthaloyl --αα--methylcyanoglycinatesmethylcyanoglycinates •• LactonesLactones •• EpoxidesEpoxides andand arenearene oxidesoxides SecondarySecondary andand TertiaryTertiary CarbinolsCarbinols
•• UseUse Pr(hfc)Pr(hfc) 3 •• MeasureMeasure 13 CC NMRNMR spectrumspectrum •• ExamineExamine shiftsshifts ofof neighboringneighboring carbonscarbons •• WorksWorks forfor diolsdiols asas wellwell ifif separatedseparated byby twotwo oror moremore carbonscarbons R OH HO R ∆∆δ ∆δ ∆δ = (R)-Pr(tfc)3 - (S)-Pr(tfc)3 YX YX
α-orientation β-orientation ∆∆δ = negative ∆∆δ = positive
Me Me OH Me OH Me OH Me OH Me
Me OH 4 BinuclearBinuclear LanthanideLanthanide --SilverSilver ReagentsReagents β β β Ln( -dik) 3 + Ag( -dik) = [Ln( -dik) 4]Ag •• EffectiveEffective forfor softsoft LewisLewis basesbases –– OlefinsOlefins –– AromaticsAromatics –– AlkynesAlkynes –– PhosphinesPhosphines –– HalidesHalides (iodide(iodide andand bromide)bromide) BinuclearBinuclear LanthanideLanthanide --SilverSilver ReagentsReagents –– OrganicOrganic SaltsSalts
β + - β [Ln( -dik) 4]Ag + R X = [Ln( -dik) 4]R + AgX(s)
•• AmmoniumAmmonium saltssalts •• IsothiouroniumIsothiouronium saltssalts •• SulfoniumSulfonium saltssalts LanthanideLanthanide ComplexesComplexes WaterWater --solublesoluble •• ChelatesChelates ofof pdtapdta (anionic(anionic ligandligand ))
CO2H
HO2C N N CO2H
HO2C •• ChelatesChelates ofof tppntppn (neutral(neutral ligandligand ))
N N
N N N N
H3C •• EffectiveEffective forfor carboxyliccarboxylic acidsacids –– absoluteabsolute configurationsconfigurations ofof aminoamino acidsacids PalladiumPalladium --AmineAmine DimersDimers
Me Me Me NMe2 Me2N Me
NMe2 Me2N Cl Cl Pd Pd Pd Pd Cl Cl
cis cis
Me NMe2 Me Cl NMe2 Pd Pd Cl Pd Pd Cl Cl Me2N Me2N Me Me trans trans -Mono- and diphosphines bind to the palladium -Can use for enantiomeric purity and absolute
H configuration (often with NOE data) Me2 Me N P - Pd * Cl P Palladium/PlatinumPalladium/Platinum ComplexesComplexes
Ph2 Ph2 O P P M Pt P P O Ph Ph2 2
-Alkenes and alkynes can displace the ethylene ligand -Enantiomeric purity PlatinumPlatinum --AmineAmine ComplexesComplexes CovalentCovalent andand IonicIonic
Ph H2 H Cl N C Cl Cl CH + Pt 3 Pt [AmH]
Cl Cl
-Olefins and allenes displace the ethylene group -Measure 195 Pt signal - used for enantiomeric purity -Substrates have two prochiral faces -If only one face binds – two 195 Pt signals -If both faces bind – four 195 Pt signals CDA Am enantiodiscriminated substrates PlatinumPlatinum --AmineAmine Am Cl Ph
Pt unsaturated ethers H Complexes Cl Me NH Complexes 2 cis
Cl Am Ph
Pt H selected cases of allenes
Cl Me NH2 trans
1 - Np Me
H H allenes, olefins, vinyl and allyl Me N 1 - Np ethers H Cl Cl + Pt AmH
Cl ionic β-olefins NH
Cl Am
Pt α-olefins NH Cl trans RhodiumRhodium DimerDimer withwith MTPAMTPA
R
R O O O O Rh Rh O O O O R RO2 = MTPA R
R R R
R R R O O O O O O O O + L O O + L O O Rh Rh Rh Rh L L Rh Rh L O O O O -L O -L O R OO R OO R OO
R R R RhodiumRhodium DimerDimer withwith MTPAMTPA
•• Olefins R H3C CH3 P O •• Phosphines X Ph X = O, S, Se •• Aryl alkyl selenides Ch R O
X •• Phosphine selenides (P=Se) H3C CH3 Ch = S, Se, Te •• Phosphorus thionates (P=S) H3C I H3C I •• Phospholene and phospholane chalcogenides X' •• Spirochalcogenuranes R
' •• Alkyl iodides, diiodobiphenyls H3 O R •• Nitriles 3 2 •• Oxiranes H H
Ph N • Oxatriazoles , thiatriazoles , tetraazoles CH3 • N N HC N O ZincZinc PorphyrinsPorphyrins ((TweezerTweezer ))
N N Zn O N N O
O N N Zn O N N
Especially effective for bifunctional substrates (diamines) DatabaseDatabase TechniquesTechniques
•• 13 CC oror 1HH shiftsshifts CH3
H H3C C N CH3 •• NN,,αα--DimethylbenzylamineDimethylbenzylamine (DMBA)(DMBA)
•• BisBis --1,31,3 --methylbenzylaminemethylbenzylamine --22-- methylpropanemethylpropane (BMBA(BMBA --pMepMe ))
Me
H H N N
Me Me StructuralStructural MotifsMotifs
OH OH
OH OH
HO Me Me Me
Me Me
OH OH OH
OH OH OAc OAc
Me Me OAc OAc
AcO Prepare and examine all OAc possible stereoisomers 13 C or 1H Database - subtract chemical shift of particular nucleus in one stereoisomer from average of value in all eight DMBA database -Difference in 13 C shifts between ( R)- and ( S)-DMBA BMBA-pMe – For assigning the stereochemistry of secondary and tertiary alcohols
Me A OH
Ph saturated secondary ∆δ ∆δ alcohols = = N negative (acyclic and cyclic) C C positive H H
O N H Me B OH
biaryl alcohols & ∆δ ∆δ Ph benzyl alcohols = = positive C C negative
Binding of BMBA-pMe C to a secondary alcohol OH saturated tertiary ∆δ ∆δ alcohols = = positive C Me C negative
Observed trends LiquidLiquid CrystalsCrystals poly(poly( γγ--benzylbenzyl --LL--glutamate)glutamate) (PBLG)(PBLG)
•• FormsForms orderedordered materialmaterial inin aa magneticmagnetic fieldfield •• PairPair ofof enantiomersenantiomers havehave differentdifferent molecularmolecular orientationsorientations inin PBLGPBLG •• ThreeThree discriminationdiscrimination mechanismsmechanisms –– ChemicalChemical shiftshift anisotropyanisotropy (least(least useful)useful) –– DifferentDifferent dipolardipolar couplingcoupling constantsconstants (( 1HH--13 C)C) –– DifferencesDifferences inin quadrupolarquadrupolar splittingsplitting (( 2H)H) (most(most useful)useful) QuadrupolarQuadrupolar SplittingSplitting •• NotNot observedobserved inin solutionsolution becausebecause ofof rapidrapid tumblingtumbling •• ObservedObserved inin orderedordered mediamedia andand extentextent ofof splittingsplitting dependsdepends onon orientationorientation relativerelative toto thethe appliedapplied magneticmagnetic fieldfield
Proton-decoupled deuterium NMR spectrum PBLGPBLG -- IncredibleIncredible VersatilityVersatility
•• OnlyOnly needneed differentdifferent packingpacking ordersorders •• DoDo notnot needneed specificspecific interactionsinteractions betweenbetween thethe substratesubstrate andand thethe liquidliquid crystalcrystal •• EffectiveEffective forfor virtuallyvirtually anyany classclass ofof compoundcompound –– IncludesIncludes aliphaticaliphatic hydrocarbonshydrocarbons •• EspeciallyEspecially effectiveeffective forfor resonancesresonances ofof nucleinuclei remoteremote toto thethe chiralchiral centercenter DeuteriumDeuterium LabelingLabeling
•• OnlyOnly needneed deuteriumdeuterium asas aa signalsignal –– betterbetter toto useuse achiralachiral reagentsreagents soso nono concernconcern aboutabout kinetickinetic resolutionresolution oror racemizationracemization
–– ConvertConvert COCO 2HH toto COCO 2CDCD 3 –– AddAdd perdeuteroperdeutero benzoylbenzoyl groupgroup (have(have oo --,, mm -- andand pp --protonsprotons asas potentialpotential probesprobes •• ProvidesProvides aa single,single, strongstrong signalsignal (or(or aa fewfew easilyeasily assignedassigned signals)signals) forfor thethe analysisanalysis OH HO ExamplesExamples D D
S S O D D D (R,R)-, ( S,S)- and ( R,S)-(meso)-
D isomer distinguished O 4
D D OH D D HO
D
-Remote chiral center -2H signal for the para-position D showed different quadrupolar OH splitting Can distinguish ( R,R,R)-, (R,R,S)-, ( S,S,R)- and ( S,S,S)- isomers PerdeuteratedPerdeuterated /Natural/Natural AbundanceAbundance 2HH
•• ComplicatedComplicated spectraspectra –– eacheach 2HH signalsignal isis aa doubletdoublet –– eacheach 2HH signalsignal maymay bebe twotwo doubletsdoublets ifif thethe enantiomersenantiomers havehave differentdifferent quadrupolarquadrupolar splittingsplitting –– cancan ’’tt predictpredict aa prioripriori thethe magnitudemagnitude ofof thethe quadrupolarquadrupolar splittingsplitting
•• ProceduresProcedures havehave beenbeen deviseddevised toto aidaid inin thethe assignmentassignment ofof 2HH spectraspectra